Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000156.6(GAMT):c.148A>C (p.Met50Leu)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA254380

8305 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 562504e1-86d3-4fa5-818a-0eecd910d7b4

Approved on: 2025-10-07

Published on: 2025-10-07

HGVS expressions

NM_000156.6:c.148A>C

NM_000156.6(GAMT):c.148A>C (p.Met50Leu)

NC_000019.10:g.1401329T>G

CM000681.2:g.1401329T>G

NC_000019.9:g.1401328T>G

CM000681.1:g.1401328T>G

NC_000019.8:g.1352328T>G

NG_009785.1:g.5225A>C

ENST00000252288.8:c.148A>C

ENST00000447102.8:c.148A>C

ENST00000640762.1:c.112+36A>C

ENST00000252288.6:c.148A>C

ENST00000447102.7:c.148A>C

NM_000156.5:c.148A>C

NM_138924.2:c.148A>C

NM_138924.3:c.148A>C

Likely Pathogenic

PP4_Strong PP3_Moderate PS3_Supporting PM3_Supporting PM2_Supporting

PM5

Evidence Links 1

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GATM Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.148A>C variant in GAMT is predicted to result in the substitution of methionine by leucine at amino acid 50 (p.Met50Leu). One individual has been reported who was homozygous for the variant and had a low creatine peak on brain MRS, elevated urinary GAA, low creatine/creatinine ratio, with DNA sequence analysis of GAMT (PMID: 17101918, 24415674) (PM3_Supporting, PP4_Strong). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.923 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level (PMID: 36413997) (PP3_Moderate). This variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications Version 2.0.0): PP4_Strong, PP3_Moderate, PS3_Supporting, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen CCDS VCEP on October 7, 2025)

PP4_Strong

Found in proband with low creatine peak on brain MRS (3pts), elevated urinary GAA (1pts), low creatine/creatinine ratio, with DNA sequence analysis of GAMT (PMID: 17101918, 24415674) (PP4_Strong)

PP3_Moderate

The computational predictor REVEL gives a score of 0.923 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level (PMID: 36413997) (PP3_Moderate).

PS3_Supporting

The p.Met50Leu variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674)

The p.Met50Leu variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts PubMed:24415674

PM3_Supporting

PMID: 17101918: Reported in the homozygous state in one patient with guanidinoacetate methyltransferase deficiency (0.5pts)

PM2_Supporting

The variant is absent in gnomAD v4.1.0. (PM2_Supporting).

PM5

A different missense variant at the same amino acid residue, p.Met50Ile, has been previously reported and interpreted as a VUS in ClinVar (Variation ID: 566179)

Curation History

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